Imidazolidinedione derivatives in diabetes treatment

ABSTRACT

A series of novel 5-substituted imidazolidinedione derivatives and their base salts with pharmacologically acceptable cations are disclosed. These particular compounds are useful in therapy as aldose reductase inhibitors for the control of certain chronic diabetic complications. 5-Naphthalimido-imidazolidine-2,4-dione and 5-[3-(4&#39;-bromo-2&#39;-fluorobenzyl)-3,4-dihydro-4-oxophthalazin-1-yl]-imidazolidine-2,4-dione represent typical and preferred member compounds. Methods for preparing all these compounds from known starting materials are provided.

TECHNICAL FIELD

This invention relates to new imidazolidinedione derivatives of interestto those in the field of medicinal chemistry and chemotherapy. Moreparticularly, it is concerned with a novel series of 5-substitutedimidazolidinedione compounds for the control of certain chroniccomplications arising from diabetes mellitus (e.g., diabetic cataracts,retinopathy and neuropathy).

BACKGROUND ART

Past attempts to obtain new and better oral antidiabetic agents have,for the most part, involved an endeavor to synthesize new compounds thatlower blood sugar levels. More recently, several studies have beenconducted concerning the effect of various organic compounds inpreventing or arresting certain chronic complications of diabetes, suchas diabetic cataracts, neuropathy and retinopathy, etc. For instance, K.Sestanj et al. in U.S. Pat. No. 3,821,383 discloses that certain aldosereductase inhibitors like1,3-dioxo-1H-benz[d,e]isoquinoline-2(3H)-acetic acid and someclosely-related derivatives thereof are useful for these purposes eventhough they are not known to be hypoglycemic. These compounds functionby inhibiting the activity of the enzyme aldose reductase, which isprimarily responsible for catalyzing the reduction of aldoses (likeglucose and galactose) to the corresponding polyols (such as sorbitoland galactitol) in the human body. In this way, unwanted accumulationsof galactitol in the lens of galactosemic subjects and of sorbitol inthe lens, retina, peripheral nervous system and kidney of diabeticsubjects are prevented or reduced. As a result, these compounds controlcertain chronic diabetic complications, including those of an ocularnature, since it is already known in the art that the presence ofpolyols in the lens of the eye leads to cataract formation andconcomitant loss of lens clarity.

DISCLOSURE OF THE INVENTION

The present invention relates to novel 5-substituted imidazolidinedionecompounds useful as aldose redutase inhibitors for the control ofcertain chronic complications arising in a diabetic subject. Morespecifically, the novel compounds of this invention are selected fromthe group consisting of 5-substituted imidazolidinedione derivatives ofthe formula: ##STR1## or a base salt thereof with a pharmacologicallyacceptable cation, wherein Z is ##STR2## wherein X is hydrogen,fluorine, chlorine, bromine, nitro, trifluoromethyl, C₁ -C₄ alkyl or C₁-C₄ alkoxy; and R is naphthylmethyl, furfuryl, thenyl or phenylalkylhaving from one to three carbon atoms in the alkyl moiety wherein saidphenylalkyl is optionally substituted with one or two identical ornon-identical substituents on the phenyl ring, said identicalsubstituents being fluorine, chlorine, bromine, trifluoromethyl, C₁ -C₄alkyl or C₁ -C₄ alkoxy and said non-identical substituents beingfluorine, chlorine, bromine, methyl, methoxy or trifluoromethyl. Thesenovel compounds are aldose reductase inhibitors and therefore, possessthe ability to reduce or inhibit sorbitol formation in the lens andperipheral nerves of diabetic subjects.

One group of compounds of the present invention of interest is that ofthe general formula I where Z is of the formula II wherein X ishydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyl, C₁ -C₄alkyl or C₁ -C₄ alkoxy. Preferred compounds within this group includethose where X is hydrogen, chlorine, bromine, nitro, methyl or methoxy.

Another group of compounds of the present invention of interest is thatof the general formula I wherein Z is of the formula III wherein R isnaphthylmethyl, furfuryl, thenyl, or phenylalkyl having from one tothree carbon atoms in the alkyl moiety wherein said phenylalkyl isoptionally substituted with one or two identical or non-identicalsubstituents on the phenyl ring, said identical substituents beingfluorine, chlorine, bromine, trifluoromethyl, C₁ -C₄ alkyl or C₁ -C₄alkoxy and said non-identical substituents being fluorine, chlorine,bromine, methyl, methoxy or trifluoromethyl. Preferred compounds withinthis group include those where R is unsubstituted or ring-substitutedphenylalkyl having from one to three carbon atoms in the alkyl moietyand more preferably, R is ring-substituted phenylalkyl having one or twochlorine atoms on the phenyl ring or a bromine atom and a fluorine atomon the phenyl ring (like 2,5-dichlorobenzyl or 4-bromo-2-fluorobenzyl,for example).

Of special interest are such typical and preferred member compounds ofthe invention as 5-naphthalimido-imidazolidine-2,4-dione and5-[3-(4'-bromo-2'-fluorobenzyl)-3,4-dihydro-4-oxophthalazin-1-yl]-imidazolidine-2,4-dione,respectively. These two compounds are both potent aldose reductaseinhibitors, in addition to being effective in lowering sorbitol levelsin the sciatic nerve and lens of diabetic subjects.

DETAILED DESCRIPTION

In accordance with the process employed for preparing the novelcompounds of this invention of the general structural formula I whereinZ is of the formula II, an appropriately substituted naphthalic acidanhydride compound of the formula: ##STR3## wherein X is as previouslydefined is condensed with 5-aminohydantoin or a hydrohalide acidaddition salt thereof to form the desired 5-substituted hydantoin finalproduct of the structural formula previously indicated. This particularreaction is normally conducted in the presence of an organic basesolvent, such as a tertiary amine like pyridine or triethylamine, byheating the two reactants together at a temperature that is in the rangeof from about 35° C. up to about 120° C. until the condensation issubstantially complete, i.e., until no more water of reaction forms andthis will usually require a period of at least about one hour. Ingeneral, substantially equimolar proportions of reactants are employed,although the ratio can vary anywhere from about 0.5 to about 2.0 mole of5-aminohydantoin per mole of starting naphthalic acid anhydride compoundwithout causing unwanted side reactions to occur to any significantdegree. Upon completion of the reaction, the desired product is theneasily isolated from the reaction mixture in a conventional manner,viz., by first concentrating same in vacuo and thereafter trituratingthe residue with a suitable solvent such as ethanol, followed by furtherpurification via recrystallization from a different solvent such astetrahydrofuran, for example.

The starting materials required for preparing the novel 5-substitutedhydantoin formula I compounds of this invention where Z is of formula IIare either known compounds which are readily available commercially,like 1,8-naphthalic acid anhydride, or they are described in theliterature like 4-bromo-1,8-naphthalic acid anhydride [H. G. Rule etal., Journal of the Chemical Society (London), p. 1764 (1937)] and3-nitro-1,8-naphthalic acid anhydride [F. Anselm et al. et al.,Chemische Berichte, Vol. 32, p. 3283 (1899)], or else they can easily besynthesized by those skilled in the art starting from common chemicalreagents and using conventional methods of organic synthesis. Forinstance, 5-aminohydantoin hydrobromide is readily prepared from theknown 5-hydroxyhydantoin [J. Abblard et al., Bulletin de la societechimique de France, p. 942 (1971)] via a three-step sequence ofreactions that is hereinafter described in detail in the experimentalsection of the specification (see Preparations A-B).

In accordance with the process employed for preparing the novelcompounds of this invention of the general structural formula I whereinZ is of the formula III, an appropriately substituted heteroaromaticaldehyde compound of the formula ##STR4## is condensed with an alkalimetal cyanide (e.g. sodium cyanide or potassium cyanide) and ammoniumcarbonate to form the desired 5-substituted imidazolidinedione finalproduct of the structural formula previously indicated. This particularreaction is normally carried out in the presence of an aqueousreaction-inert polar organic solvent medium in which both the reactantsand reagents are mutually miscible. Preferred organic solvents for usein this connection include cyclic ethers such as dioxane andtetrahydrofuran, lower alkylene glycols like ethylene glycol andtrimethylene glycol, water-miscible lower alkanols such as methanol,ethanol and isopropanol, as well as N,N-di(lower alkyl) loweralkanoamides like N,N-dimethyl-formamide, N,N-diethylformamide andN,N-dimethylacetamide, etc. In general, the reaction is conducted at atemperature that is in the range of from about 50° C. up to about 150°C. for a period of about two hours to about four days. Although theamount of reactant and reagents employed in the reaction can vary tosome extent, it is preferable to employ at least a slight molar excessof both the alkali metal cyanide and ammonium carbonate reagents withrespect to the heteroaromatic aldehyde starting material in order toeffect maximum yield. Upon completion of the reaction, the desiredproduct is easily isolated in a conventional manner, e.g., by firstdiluting the reaction mixture with ice water, followed by acidificationto afford the desired 5-substituted imidazolidine compound in the formof a readily-recoverable precipitate. Further purification can then becarried out by such means as silica gel column chromatography and thelike, in addition to standard recrystallization procedures.

The aldehyde starting materials (i.e., heteroaromatic aldehyde compoundsof structural formula V) are, for the most part, known compounds and caneasily be synthesized by those skilled in the art from common organicchemicals by using conventional methods of organic synthesis. Forinstance,3-(4'-bromo-2'-fluorobenzyl)-3,4-dihydro-4-oxophthalazine-1-carboxaldehydeis readily prepared from the known 1-methyl-3,4-dihydro-4-oxophthalazinevia a four-step sequence of reactions that is hereinafter described indetail in the experimental section of the specification (seePreparations C-F).

The chemical bases which are used as reagents in this invention toprepare the aforementioned pharmaceutically acceptable base salts arethose which form non-toxic base salts with the herein described5-substituted imidazolidinedione compounds such as5-[3-(4'-bromo-2'-fluorobenzyl)-3,4-dihydro-4-oxophthalazin-1-yl]-imidazolidine-2,4-dione,for example. These particular non-toxic base salts include those derivedfrom such pharmacologically acceptable cations as sodium, potassium,calcium and magnesium, etc. These salts can easily be prepared by simplytreating the aforementioned 5-substituted imidazolidinedione compoundswith an aqueous solution of the desired pharmacologically acceptablecation, and then evaporating the resulting solution to dryness,preferably under reduced pressure. Alternatively, they may also beprepared by mixing lower alkanolic solutions of the acidic compounds andthe desired alkali metal alkoxide together, and then evaporating theresulting solution to dryness in the same manner as before. In eithercase, stoichiometric quantities of reagents are preferably employed inorder to ensure completeness of reaction and maximum yields of thedesired final product.

As previously indicated, the 5-substituted imidazolidinedione compoundsof this inventon are readily adapted to therapeutic use as aldosereductase inhibitors for the control of certain chronic diabeticcomplications, in view of their ability to reduce lens and peripheralnerve sorbitol levels in diabetic subjects to a statisticallysignificant degree. For instance,5-[3-(4'-bromo-2'-fluorobenzyl)-3,4-dihydro-7-oxophthalazin-1-yl]-imidazolidine-2,4-dione,a typical and preferred agent of the present invention, has been foundto inhibit the formation of sorbitol levels in both the sciatic nerveand lens of diabetic rats to a significantly high degree when given bythe oral route of administration at a dose level of 25 mg./kg.Furthermore, the herein described compounds of this invention can beadministered by either the oral, topical or parenteral routes ofadministration. In general, these compounds are ordinarily administeredin dosages ranging from about 0.50 mg. to about 50 mg. per kg. of bodyweight per day, although variations will necessarily occur dependingupon the weight and condition of the subject being treated and theparticular route of administration chosen.

These compounds may be administered either alone or in combination withpharmaceutically acceptable carriers by the various routes previouslyindicated, and such administration can be carried out in either singleor multiple dosages. More particularly, the compounds of this inventioncan be administered in a wide variety of different dosage forms, i.e.,they may be combined with various pharmaceutically-acceptable inertcarriers in the form of tablets, capsules, lozenges, troches, hardcandies, powders, sprays, aqueous suspensions, injectable solutions,elixirs, syrups, and the like. Such carriers include solid diluents orfillers, sterile aqueous media and various non-toxic organic solvents.In general, the compounds of the invention will be present in suchdosage forms at concentration levels ranging from about 0.5% to about90% by weight of the total composition to provide the desired unitdosage.

For oral administration, tablets containing various excipients such assodium citrate, calcium carbonate and calcium phosphate may be employedalong with various disintegrants such as starch and preferably potato ortapioca starch, alginic acid and certain complex silicates, togetherwith binding agents such as polyvinylpyrrolidone, gelatin and acacia.Additionally, lubricating agents such as magnesium stearate, sodiumlauryl sulfate and talc are often very useful for tabletting purposes.Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules; preferred materials in thisconnection also include the high molecular weight polyethylene glycols.When aqueous suspensions and/or elixirs are desired for oraladministration, the essential active ingredient therein may be combinedwith various sweetening or flavoring agents, coloring matter or dyes,and if so desired, emulsifying and/or suspending agents as well,together with such diluents as water, ethanol, propylene glycol,glycerin and various combinations thereof.

For parenteral administration, solutions of these 5-substitutedimidazolidinediones in sesame or peanut oil or in aqueous propyleneglycol or N,N-dimethylformamide may be employed, as well as sterileaqueous solutions of the corresponding water-soluble, alkali metal oralkaline-earth metal salts previously enumerated. Such aqueous solutionsshould be suitably buffered if necessary and the liquid diluent firstrendered isotonic with sufficient saline or glucose. These particularaqueous solutions are especially suitable for intravenous,intramuscular, subcutaneous and intraperitoneal injection. In thisconnection, the sterile aqueous media employed are all readilyobtainable by standard techniques well-known to those skilled in theart. Additionally, it is also possible to administer the aforesaid5-substituted imidazolidine compounds topically via an appropriateophthalmic solution (0.5-2.0%) applied dropwise to the eye.

The activity of the compounds of the present invention, as agents forthe control of chronic diabetic complications, is determined by theirability to successfully pass one or more of the following standardbiological or pharmacological tests, viz., (1) measuring their abilityto inhibit the enzyme activity of isolated aldose reductase; (2)measuring their ability to reduce or inhibit sorbitol accumulation inthe sciatic nerve and lens of acutely streptozotocinized (i.e.,diabetic) rats; (3) measuring their ability to reverse already-elevatedsorbitol levels in the sciatic nerve and lens of chronicstreptozotocin-induced diabetic rats; (4) measuring their ability toprevent or inhibit galactitol formation in the lens of acutelygalactosemic rats, and (5) measuring their ability to delay cataractformation and reduce the severity of lens opacities in chronicgalactosemic rats.

PREPARATION A

A mixture consisting of 2.57 g. (0.022 mole) of 5-hydroxyhydantoin[prepared by reducing parabanic acid (oxalylurea or imidazoletrione)with potassium borohydride according to the method described by J.Abblard et al in Bulletin de la societe chimique de France,] p. 942(1971)] and 30 ml. of thionyl chloride containing three drops ofN,N-dimethylformamide was refluxed for a period of approximately 16hours (overnight). Upon completion of this step, the resulting reactionmixture (which contained 5-chlorohydantoin) was evaporated to drynessunder reduced pressure and the residue slurried in 30 ml. ofnitromethane, followed by the addition thereto of a solution consistingof 3.3 g. (0.022 mole) of benzyl carbamate dissolved in 50 ml. ofnitromethane. After warming the final reaction mixture to 50° C. for aperiod of three hours, there were obtained, after evaporation andcrystallization of the residue from hot water, 1.97 g. (36%) of pure5-benzyloxycarbonylaminohydantoin, m.p. 178°-180° C. (decomp.); massspectrum, m/e 249.

Anal. Calcd. for C₁₁ H₁₁ N₃ O₄ : C, 53.01; H, 4.45; N, 16.86. Found: C,52.84; H, 4.60; N, 16.89.

PREPARATION B

A mixture consisting of 100 mg. (0.004 mole) of5-benzyloxycarbonylaminohydantoin (the product of Preparation A) and 1.0ml. of 30% hydrobromic acid in glacial acetic acid was allowed to standat room temperature (˜20° C.) for a period of 30 minutes. Uponcompletion of this step., the product was precipitated from the reactionmixture by the addition of diethyl ether and there was obtained 72 mg.(92%) of pure 5-aminohydantoin hydrobromide, m.p. >250° C.; massspectrum, m/e 115.

Anal. Calcd. for C₃ H₅ N₃ O₂.HBr: C, 18.38; H, 3.08; N, 21.44. Found: C,18.51; H, 3.04; N, 21.24.

PREPARATION C

In a 250 ml. three-necked, round-bottomed reaction flask equipped withmagnetic stirring bar, glass stopper and reflux condenser, there wereplaced 2.5 g. (0.0156 mole) of 1-methyl-3,4-dihydro-4-oxophthalazine [W.S. Trahanovsky et al., Journal of Organic Chemistry, Vol. 31, p. 2033(1966)] dissolved in 30 ml. of glacial acetic acid, followed by theaddition of 34.28 g. (0.0625 mole) of ceric ammonium nitrate dissolvedin 120 ml. of glacial acetic acid/water (1:1 by volume). The stirredmixture was then heated in an oil bath at 110° C. for a period of 45minutes. Upon completion of this step, the reaction mixture was pouredinto 200 ml. of water containing some ice and thereafter extracted withthree-100 ml. portions of ethyl acetate. The combined ethyl acetateextracts were then successively washed with two-50 ml. portions of 2Naqueous sodium hydroxide, two-50 ml. portions of water and one-50 ml.portion of saturated aqueous sodium chloride, followed by drying overanhydrous magnesium sulfate. After removal of the drying agent by meansof filtration and the solvent by means of evaporation under reducedpressure, there were obtained 3.76 g. of solid material as the residue.The latter was then dissolved in 100 ml. of hot methanol andchromatographed on a silica gel column, using 20% ethyl acetate/hexaneas the eluant. The column had been prepared by first adding threeteaspoonfuls of silica gel (70-120 mesh size) to the hot methanolicsolution, followed by concentration in vacuo and then drying of theresulting residue under a high vacuum. The dried material was next addedto a gravity column (230 mm.×70 mm.) and eluted with the aforesaideluant, collecting 25 ml. fractions. Fraction Nos. 127-340 were combinedand subsequently concentrated in vacuo to yield 436.5 mg. (16%) of3,4-dihydro-4-oxophthalazine-1-carboxaldehyde; mass spectrum, m/e 174.1(100%).

Anal. Calcd. for C₉ H₆ N₂ O₂.0.125H₂ O: C, 61.28; H,

3.57; N, 15.88. Found: C, 61.46; H, 3.40; N, 15.85.

PREPARATION D

In a 50 ml. round-bottomed reaction flask equipped with magneticstirring bar and nitrogen-inlet tube, there were placed 436.5 mg (0.0025mole) of 3,4-dihydro-4-oxophthalazine-1-carboxaldehyde (the product ofPreparation C) and 10 ml. of pure methanol (HPLC grade), followed by theaddition of two drops of concentrated sulfuric acid. The resultingmixture was then stirred at room temperature (˜20° C.) for a period offour hours. Upon completion of this step, the reaction mixture wasfiltered to recover the precipitated white solid material, which wasthereafter dried in a vacuum to constant weight. In this manner, therewas eventually obtained 124.8 mg. (23%) of the dimethyl acetal of3,4-dihydro-4-oxophthalazine-1-carboxaldehyde; mass spectrum, m/e 221.0,189.1 (100%).

PREPARATION E

In a dry 50 ml. three-necked, round-bottomed flask reaction flaskequipped with magnetic stirring bar, nitrogen-inlet tube, rubber septumand glass stopper, there was placed 40.8 mg. (0.00085 mole) of sodiumhydride and 3 ml. of dry tetrahydrofuran, followed by the addition of124.8 mg. (0.00057 mole) of the dimethyl acetal of3,4-dihydro-4-oxophthalazine-1-carboxaldehyde (the product ofPreparation D) dissolved in 6 ml. of dry tetrahydrofuran. The resultingmixture was then stirred for a period of 30 minutes, followed by theaddition of 168.1 mg. (0.00063 mole) of 4-bromo-2-fluorobenzyl bromidein 3 ml. of dry tetrahydrofuran. The final reaction mixture was thenstirred at room temperature (˜20° C.) for a period of 18 hours prior tothe work-up. This was accomplished by first diluting the reactionmixture with 1N hydrochloric acid/water (2 ml./10 ml.) and thenextracting the diluted mixture with three-10 ml. portions of ethylacetate. The organic extracts were then combined and dried overanhydrous sodium sulfate. After removal of the drying agent by means offiltration and the solvent by means of evaporation under reducedpressure, there was obtained, after first drying in vacuo, 240.0 mg. ofa yellow solid as the residual material. This material was thenchromatographed on a silica gel flash column (20 mm.×175 mm.), using agradient solvent system beginning with 10% ethyl acetate/hexane (200ml.), then 20% ethyl acetate/hexane as the eluant and collecting 5 ml.samples. Fraction Nos. 35-50 were combined and subsequently concentratedin vacuo to yield 110.1 mg. (32%) of the dimethyl acetal of3-(4'-bromo-2'-fluorobenzyl)-3,4-dihydro-4-oxophthalazine-1-carboxaldehyde;mass spectrum, m/e 406.1, 408.1 (m+2), 188.9, 175.1, 75.0 (100%).

PREPARATION F

The procedure described in Preparation E is repeated except that2,5-dichlorobenzyl bromide is the alkylating agent of choice employed inlieu of 4-bromo-2-fluorobenzyl bromide, using the same molar proportionsas before. In this particular case, the corresponding final productobtained is the dimethyl acetal of3-(2',5'-dichlorobenzyl)-3,4-dihydro-4-oxophthalazine-1-carboxaldehyde.

PREPARATION G

In a 25 ml. round-bottomed reaction flask containing a magnetic stirringbar, there were placed 110.1 mg (0.00027 mole) of the dimethyl acetal of3-(4'-bromo-2'-fluorobenzyl)-3,4-dihydro-4-oxophthalazine-1-carboxaldehyde(the product of Preparation E) and 5 ml. of trifluoroacetic acid, andthe resulting solution was stirred at room temperature (˜20° C.) for aperiod of 15 minutes. Upon completion of this step, the resultingreaction mixture was concentrated in vacuo and the brown solid materialso obtained was subjected to silica gel column chromatography. This wasaccomplished by passing the material through a short silica gel gravitycolumn (130 mm.×12 mm.), using 20% ethyl acetate/hexane as the solventfor the column and as the eluant for same. In this manner, there wasobtained, after combining the desired fractions, concentrating in vacuoand drying under a high vacuum, 92.7 mg. (95%) of pure3-(4'-bromo-2'-fluorobenzyl)-3,4-dihydro-4-oxophthalazine-1-carboxaldehyde;mass spectrum, m/e 360.1, 362.1 (m+2), 103.1 (100%).

PREPARATION H

The procedure described in Preparation G is repeated except that3-(2',5'-dichlorobenzyl)-3,4-dihydro-4-oxophthalazine-1-carboxaldehyde(the product of Preparation F) is the starting material employed inplace of3-(4'-bromo-2'-fluorobenzyl)-3,4-dihydro-4-oxophthalazine-1-carboxaldehyde,using the same molar proportions as before. In this particular case, thecorresponding final product obtained is 3-(2',5'-dichlorobenzyl)-3,4,-dihydro-4-oxophthalazine-1carboxaldehyde.

EXAMPLE 1

A mixture consisting of 250 mg. (0.0013 mole) of 5-aminohydantoinhydrobromide (the product of Preparation B) and 200 mg. (0.001) mole of1,8-naphthalic acid anhydride in 12.5 ml. of pyridine was heated at 40°C. for a period of eight hours and then at 120° C. for a period of onehour. Upon completion of this step, the resulting reaction mixture wasevaporated to dryness under reduced pressure and the residue trituratedwith ethanol, followed by recrystallization from tetrahydrofuran toultimately give 160 mg. (54%) of pure5-naphthalimido-imidazolidine-2,4-dione as the hemihydrate, m.p.290°-292° C.; mass spectrum, m/e 295.

Anal. Calcd. for C₁₅ H₉ N₃.0.5H₂ O: C, 59.21; H, 3.31; N, 13.81. Found:C, 59.44;.H, 3.69; N, 13.66.

EXAMPLE 2

The procedure described in Example 1 is repeated except that4-bromo-1,8-naphthalic acid anhydride [H. G. Rule et al., Journal of theChemical Society (London), p. 1764 (1937)] is the starting materialemployed in place of 1,8-naphthalic acid anhydride, using the same molarproportions as before. In this particular case, the corresponding finalproduct obtained is 5-(6'-bromonaphthalimido)-imidazolidine-2,4-dione.

EXAMPLE 3

The procedure described in Example 1 is repeated except that3-nitro-1,8-naphthalic acid anhydride [F. Anselm et al., ChemischeBerichte, Vol. 32, p. 3283 (1899)] is the starting material employed inplace of 1,8-naphthalic acid anhydride, using the same molar proportionsas before. In this particular case, the

corresponding final product obtained is5-(5'-nitronaphthalimido)-imidazolidine-2,4-dione.

EXAMPLE 4

In a 50 ml. round-bottomed reaction flask containing a magnetic stirringbar, there were placed 288.3 mg. (0.00079 mole) of3-(4'-bromo-2'-fluorobenzyl)-3,4-dihydro-4-oxophthalazine-1-carboxaldehyde(the product of Preparation G) and 5 ml. of absolute ethanol, followedby the addition of 104.2 mg (0.0016 mole) of potassium cyanide and 374.6mg (0.0039 mole) of powdered ammonium carbonate and 5 ml. of water tothe stirred suspension. A reflux condenser with a nitrogen-inlet tubewas then attached, and the reaction flask and contents were next placedin an oil bath that had been preheated to 70° C. The reaction mixturewas then allowed to stir at 70° C. for a period of approximately 16hours (i.e., overnight), while under a nitrogen atmosphere. Uponcompletion of this step, the resulting mixture was poured into 30 ml. ofice and water to form a milky yellow suspension having a pH value of pH11.0. The pH was then carefully re-adjusted to pH 2.0 by the slowaddition of 6N hydrochloric acid causing a crystalline precipitate toform. The latter material was subsequently recovered by means of suctionfiltration and air dried to constant weight, followed by drying under ahigh vacuum to give 284.8 mg. of a yellow solid. The latter material wasthen chromatographed on a short silica gel gravity column (130×20 mm.),using 20% ethyl acetate/hexane as the solvent for the column and as theeluant for same, and collecting 5 ml. samples. Fraction Nos. 8-17 werecombined and subsequently concentrated in vacuo to yield 101.6 mg. of acrystalline yellow solid. Recrystallization of the latter material fromethyl acetate/petroleum ether then gave 47.6 mg. (14%) of pure5-[3-(4'-bromo-2'-fluorobenzyl)-3,4-dihydro-4-oxophthalazin-1-yl]-imidazolidine-2,4-dioneas a quarter hydrate in the form of a pale yellow solid melting at184°-186° C. The pure product was further characterized by means of massspectroscopy and nuclear magnetic resonance data, in addition toelemental analysis.

Anal. Calcd. for C₁₈ H₁₂ N₄ O₃ BrF.0.25H₂ O: C, 49.61, H, 2.89; N,12.85. Found: C, 49.40; H, 2.93, N, 12.53.

EXAMPLE 5

The procedure described in Example 4 is repeated except that3-(2',5'-dichlorobenzyl)-3,4-dihydro-4-oxophthalazine-1-carboxaldehyde(the product of Preparation H) is the starting material employed inplace of3-(4'-bromo-2'-fluorobenzyl)-3,4-dihydro-4-oxophthalazine-1-carboxaldehyde,using the same molar proportions as before. In this particular case, thecorresponding final product obtained is5-[3-(2',5'-dichlorobenzyl)-3,4-dihydro-4-oxophthalazin-1-yl]imidazolidine-2,4-dione.

EXAMPLE 6

The following 5-substituted imidzolidinedione derivatives of Examples 1and 4, respectively, were tested for their ability to reduce or inhibitaldose reductase enzyme activity via the procedure of S. Hayman et al.,as described in the Journal of Biological Chemistry, Vol. 240, p. 877(1965) and as modified by K. Sestanj et al. in U.S. Pat. No. 3,821,383.In each case, the substrate employed was partially purified aldosereductase enzyme obtained from human placenta. The results obtained witheach compound are expressed below in terms of the percent inhibition ofenzyme activity with respect to the various concentration levels tested:

    ______________________________________                                                 Percent Inhibition (%)                                               Compound   10.sup.-4 M                                                                            10.sup.-5 M                                                                           10.sup.-6 M                                                                          10.sup.-7 M                                                                         10.sup.-8M                           ______________________________________                                        Product of Ex. 1                                                                         100      59      17      6    --                                   Product of Ex. 4                                                                         --       91      86     72    20                                   ______________________________________                                    

EXAMPLE 7

5-[3-(4'-Bromo-2'-fluorobenzyl)-3,4-dihydro-4-oxophthalazin-1-yl]-imidazolidine-2,4-dione,the product of Example 4, was tested for its ability to reduce orinhibit sorbitol accumulation in the sciatic nerve and lens ofstreptozotocinized (i.e., diabetic rats) by the procedure essentiallydescribed in U.S. Pat. No. 3,821,383. In the present study, the amountof sorbitol accumulation in the sciatic nerve and lens of each testanimal was measured 27 hours after the induction of diabetes. Thecompound was then administered orally at 25 mg./kg. at intervals of 4, 8and 24 hours after the administration of streptozotocin. The resultsobtained in this manner are presented in terms of the percent inhibition(%) afforded by the test compound as compared to the case where nocompound was administered (i.e., the control or untreated animal wheresorbitol levels normally rise from approximately 50-100 mM/g. tissue toas high as 400 mM/g. tissue in the 27-hour test period). In this manner,it was found that 5-[3-(4'-bromo-2'-fluorobenzyl)-3,4-dihydro-4-oxophthalazin-1-yl]-imidazolidine-2,4-dioneafforded a 61% reduction in the accumulated sorbitol levels in thesciatic nerve of diabetic rats and a 36% reduction in the lens.

What is claimed is:
 1. A 5-substituted imidazolidinedione compound of the formula: ##STR5## or a base salt thereof with a pharmacologically acceptable cation, wherein Z is ##STR6## wherein X is hydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyl, C₁ -C₄ alkyl or C₁ -C₄ alkoxy; andR is naphthylmethyl, furfuryl, thenyl or phenylalkyl having from one to three carbon atoms in the alkyl moiety wherein said phenylalkyl is optionally substituted with one or two identical or non-identical substituents on the phenyl ring, said identical substituents being fluorine, chlorine, bromine, trifluoromethyl, C₁ -C₄ alkyl or C₁ -C₄ alkoxy and said non-identical substituents being fluorine, chlorine, bromine, methyl, methoxy or trifluoromethyl.
 2. A compound as claimed in claim 1 wherein Z is of the formula II.
 3. A compound as claimed in claim 1 wherein Z is of the formula III.
 4. A compound as claimed in claim 2 wherein X is hydrogen.
 5. A compound as claimed in claim 2 wherein X is chlorine.
 6. A compound as claimed in claim 2 wherein X is bromine.
 7. A compound as claimed in claim 2 wherein X is nitro.
 8. A compound as claimed in claim 2 wherein X is C₁ -C₄ alkyl.
 9. A compound as claimed in claim 2 wherein X is C₁ -C₄ alkoxy.
 10. A compound as claimed in claim 3 wherein R is unsubstituted phenylalkyl having from one to three carbon atoms in the alkyl moiety.
 11. A compound as claimed in claim 3 wherein R is ring-substituted phenylalkyl having from one to three carbon atoms in the alkyl moiety.
 12. A compound as claimed in claim 11 wherein R is ring-substituted phenylalkyl having one or two chlorine atoms on the phenyl ring.
 13. A compound as claimed in claim 11 wherein R is ring-substituted phenylalkyl having a bromine atom and a fluorine atom on the phenyl ring.
 14. A compound as claimed in claim 13 wherein R is 4-bromo-2-fluorobenzyl.
 15. 5-Naphthalimido-imidazolidine-2,4-dione.
 16. 5-[3-(4'-Bromo-2'-fluorobenzyl)-3,4-dihydro-4-oxophthalazin-1-yl]-imidazolidine-2,4-dione.
 17. A pharmaceutical composition suitable for oral, topical or parenteral administration comprising a pharmaceutically acceptable carrier and a compound as claimed in claim 1 in an amount effective for the treatment of diabetes-associated chronic complications.
 18. A method for treating a diabetic subject to prevent or alleviate chronic complications arising in said subject, which comprises administering to said diabetic subject an effective amount of a compound as claimed in claim
 1. 